1. Field of the Invention
The invention is related to scanning probe microscopy, and more specifically, a neural circuit probe based on probes used in scanning ion conductance microscopy and multi-electrode arrays.
2. Description of the Related Art
(Note: This application references a number of different publications as indicated throughout the specification by one or more reference numbers within brackets, e.g., [x]. A list of these different publications ordered according to these reference numbers can be found below in the section entitled “References.” Each of these publications is incorporated by reference herein.)
Recently, it has been argued that studying neuron networks at the mesoscopic scale may be a path to understanding Alzheimer's disease and other neurodegenerative diseases where the interaction of neurons is believed to be key to the pathophysiology [1]. Multi-electrode arrays (MEAs) are powerful tools for monitoring the electrical behavior of small collections of neurons in mesoscopic neuron networks. MEAs made it possible to highlight synaptic dysfunction in the hippocampus of a transgenic mouse models of Alzheimer's disease in young animals well before the typical amyloid or tau pathology was evident [2]. MEAs were also used to measure the spatio-temporal patterns of spontaneous interictal and evoked seizure-like events and the mechanisms underlying seizure onset and propagation in human epileptic postoperative cortical tissue [3]. A new company, Neuroproof, is using MEAs for phenotypic drug screening.
One limitation of MEAs is that there has been no way to unambiguously identify the contribution of a specific neuron to the network behavior or to analyze the biochemistry of neurons that are found to play a special role in the network.
One way to identify specific cells such as individual neurons is through scanning probe microscopy. Scanning probe microscopy is a family of related techniques for providing images of surfaces and for providing information about the mechanical, electrical and magnetic properties of surfaces. For example, atomic force microscopy (AFM) provides for very high-resolution scanning of surfaces, on the order of nanometers. Another example is scanning ion conductance microscopy (SICM), which provides high resolution images of soft surfaces such as cell surfaces without contacting the surfaces.
Recently, new SICM [4] probes have been developed that extend its capabilities to include local measurements of specific ion concentrations [5], pH [6,7], electrical potential gradients [8], oxygen consumption [9], cell mechanical properties [10-12], the delivery of molecules for quantitative receptor mapping [13] and electroporation [14]. These new probes and techniques, reported in just the past two years, have been used on a variety of cell types including neurons. Earlier work on cells, beginning with the pioneering work of Korchev and his group, and including work on protein localization on the surface of cells, is well summarized in recent reviews [15-17].
Thus, there is a need in the art for combining these technologies. The present invention satisfies this need.